For many years, depressions were considered to be related to decreased activity of central adrenergic processes, and the antidepressant activity of imipramine-like drugs was suggested to result from an inhibition of noradrenaline re-uptake. Accordingly, the efforts concentrated on finding drugs which potentiated noradrenaline by preventing re-uptake. Among phthalans described in U.S. Pat. No. 2,467,675 it was found that the most potent compound having a noradrenaline potentiating effect was a phthalane having methyl groups in position 3 of the ring structure, no substituents in the phenyl ring, an unsubstituted phenyl ring in position 1, and a monomethylaminopropyl group attached to position 1. In fact, only compounds having two methyl groups at position 3 were found to be very potent potentiators of noradrenaline; P. V. Petersen et al.; Acta pharmacol. et toxicol. 1966, Vol. 24, pg. 121.
On the basis of recent advances in pharmacology and biochemistry of antidepressants and depressions, Carlsson et al.: "Effect of antidepressant drugs on the depletion of intraneuronal brain 5-hydroxytryptamine stores caused by 4-methyl-.alpha.-ethyl-meta-tyramine": Euro. J. Pharmacol., 1969, 5, pg. 357-366, suggested that blockade of 5-hydroxytryptamine re-uptake is involved in the mood-elevating action of tricyclic antidepressants, whereas blockade of noradrenaline re-uptake promotes drive in the depressed patients.
Also Lapin & Oxenkrug: "Intensification of the central serotoninergic processes as a possible determinant of the thymoleptic effect": Lancet, 1969, 1, pg. 132-136, suggest that the mood-elevating effect of monoamineoxidase inhibitors and of electroconvulsive therapy is related to an intensification of serotoninergic processes in the brain.